Process for preparing novel cyclic amines



United States Patent 3,094,534 PROCESS FOR PREPARING NOVEL CYCLIC AMINESRudolf Griot, Basel, and Theodor Wagner-Jauregg, Zofingen, Switzerland,assignors to Siegfried Aktiengesellschaft, Zofingen, Switzerland NoDrawing. Filed Mar. 6, 1961, Ser. No. 93,333

14 Claims. (Cl. 260-313) acetone oxime CHr-CH-CH:

7 CH==CH NOH is treated with zinc dust in glacial acetic acid atelevated temperatudes in the range from about 65 C. to about 110 C. toobtain a mixture of compounds (I) and (E) corresponding to the followingformulas:

This mixture may be separated by usual means, e.g. fractionalrecrystallisation from appropriate solvents or fractional distillationto yield the individual compounds (I) and (E). If desired, theunsaturated cyclic amines (I) and (E) maybe reduced to yield thecorresponding saturated compounds (II) and (F) Ir CHz-CH-CH:

on. on on CH-CHNH on r eaten-0n,

c 1 on-on, I on? n-Nrr In a further process step the above cyclic aminesare N-alkylated, e.g. by means of an alkyl halide, preferably a methylhalide; to produce the corresponding N-alkyl derivatives having thegeneral formulas in which R represents an alkyl radical containing from1 to 4 carbon atoms.

The optional reduction of the unsaturated amines may be effected by useof lithium aluminum hydride in an appropriate solvent, e.g.tetrahydrofuran, of amalgamated zinc and hydrochloric acid, or bycatalytical hydrogenation, e.g. in presence of palladium or platinumcatalysts at elevated or normal pressures in suitable solvents.

The compounds of the present invention are useful therapeutics, e.g. fortreatment of Parkinsons disease and injuries caused by nicotine. Thus,the hydroiodide of 3,N dimethyl-S-hydroxy-Q-azobicyclo-[3,3,0]-octanee.g. in the mice test by subcutaneous administration of 27 mg./kg.protected fromdeath 50% of the test animals to which 30 minutes beforemg/kg. of nicotine tartrate had been injected intraperitoneally. Forcomparison, the same protective doses of Parpanit (l-phenylcyclopentanecarboxylic acid Z-diethylaminoethylester hydrochloride) and Diparcol(101-(2-diethylaminoethyl)-phenothiazine) were 200 mg. and 400 mg./kg.respectively.

Example 1 To 460 g. of M-cyclopentenyl acetone oxime dissolved in oneliter of glacial acetic acid 423 g. of zinc dust are added portionwiseat a temperature of about 50 C. with vigorous stirring, whereupon thetemperature is raised to C. and left at this temperature for further 16hours. The solution is filtered while still hot and then the acetic acidis distilled off under reduced pressure. The residue is extracted withpetroleum ether to remove unreacted starting materials and thereuponmade alkaline by addition of 30% sodium hydroxyde solution. Theseparating oil .is removed and the aqueous phase extracted withchloroform. The combined oil and chloroform extracts are dried overanhydrous sodium sulfate. After removal of the solvent by distillationthe residue is distilled under 7 high vacuum. A fraction of 212 g.boiling beyond /0.3 mm. is recovered which solidifies almost completely.Recrystallisation of this fraction from hot ben- Zine yields crystalline3-methyl-8-hydroXy-2+azabicyclo- [3,3,01-octene-(2) resp. -(3) (I).After evaporation of the mother liquors there remain 14 g. of a fractionboiling at 36 C./ 3 mm.; n =l.4750(3-methyl-2-azabicyclo-[3,3,0]-octene-(2) resp. -(3) (E), as well as afurther crop of (I). The total yield of amine (I) is g, i.e. 25%calculated on the starting oxime or 31% calculated on the reacted oxime.

Compound (I) may be recrystallised from ethyl acetate or benzine. Itforms colorless, triclinic prisms melting at 75 C. It sublimes underreduced pressure and is readily soluble in Water, ether, chloroform,alcohol, methanol and tetrahydrofuran.

Analysis.-Calc. for CH ON: C, 69.03%; H, 9.37%; N, 10.05%. Found: C,69.10%; H, 9.42%; N, 10.10%. By treatment with suitable optically activeacids, e.g. tartaric acid the optical antipodes of (I) are obtained asoily substances. [cc] =+l57, resp. 157 .(CHC1 c.=1.3

Amine (E) alternatively may be isolated from the prerun of the abovedistillation under high vacuum. Its separation from amine (I) furthercan be effected due to its volatility with steam. It can be purified bydistillation over metallic sodium. B.P. 167 C., n =1.4754, d =0.9349.

Analysis.-Calc. for CH N: C, 78.1%; H, 10.65%. Found: C, 78.4%; H,10.81%.

The picrate melts at 181 C.

3 Example 2 A solution of 0.1 mole (13.9 g.) 3-methyl-8-hydroxy-2-azabicyclo-[3,3,0]-octene (I) in glacial acetic acid was hydrogenatedin the presence of a palladium-noritecatalyst under about 500 p.s.i. at70 C. 3-methyl- 8- hydroxy-Z-azabicyclo-[3,3,0]-octane (II) was obtainedin theoretical yield, M.P.=75 (from benzine). The compound sublimesreadily and has similar solubility properties as compound I. Mixedmelting point with (I): 55-58 C.

Analysis.-Calc. for CH ON: C, 68.0%; H, 10.71%; N, 9.9%. Found: C,67.6%; H, 10.65%; N, 9.9%.

Example 3 A solution of 10 g. of amine (I) was dropped into a suspensionof 1.5 g. of LiAlH in tetrahydrofuran. The mixture was refluxed forabout 5 hours and then recovered in the usual manner, whereby thesaturated amine (II). was obtained in quantitative yield. The productwas identical with that of Example 2.

Example 4 One mole of compound I was refluxed for about 8 hours withamalgamated Zinc and hydrochlodic acid. The dihydro compound (II) wasobtained in quantitative yield. M.P.=75 C.; the pier-ate melts at 158 C.

Example 5 By gently heating compound (I) with methyl iodide thehydroiodide of the N-monomethyl-derivative of (I) is formed, which afterrecrystallisation from methanol/ ethyl acetate melts at 133 C-.

With excessive methyl iodide in 2 N NaOH the iodomethy-late is obtainedwhich after crystallisation from alcohol or ether melts at 212214 C.

Example 7 In a similar manner as described in Example 6 the N-methylderivative of (II) is obtained. The hydroiodi-de ofN,3-dimethyl-8-l1ydroxy12-azabicyclo [3,3,0] octane melts at 146 C.

Similarly, the hydroiodide of the N-methyl derivative of compound F isobtained which has a melting point of l35l37 C. Further in analogous waythe N-ethyl-S- methyl-S-hydroxy-Z-azabicyclo-[3,3,0]-octane (MP. of thehydrochloride=112 C.) may be prepared.

We claim:

1. A process for preparing cyclic amines, which comprises treating n-cyclopentenyl acetone oxime in acetic acid with zinc dust at elevatedtemperatures and recovering and separating the amines thus produced fromthe reaction mixture.

reagent selected from the group consisting of lithium aluminum hydride,hydrogen in the presence of a palladium catalyst, hydrogen in thepresence of a platinum catalyst, and zinc and hydrochloric acid.

3. A process for preparing cyclic amines which comprises treating n-cyclopentenyl ace-tone oxime in acetic acid with zinc dust at elevatedtemperatures, isolating from the reaction mixture an amine with theempirical formula of C H NO and reducing this compound by a reagentselected from the group consisting of lithium aluminum hydride, hydrogenin the presence of a palladium catalyst, hydrogen in the presence of aplatinum catalyst, and zinc and hydrochloric acid, to yield3-methyl-8-hydroxy-Z-azabicyclo-octane, and N-alkylating the product ofsaid reduction stage by use of a methyl halide.

4. A process for preparing cyclic amines which comprises treating n-cyclopentenyl acetone oxime in acetic acid with zinc dust at elevatedtemperatures, isolating from the reaction mixture an amine with theempirical formula of C H NO, N-alkylating this compound by use of amethyl halide, and reducing the N-alkylated product by a reagentselected from the group consisting of lithium aluminum hydride, hydrogenin the presence of a palladium catalyst, hydrogen in the presence of aplatinum catalyst, and zinc and hydrochloric. acid.

5. A process for preparing cyclic amines which comprises treating A-cyclopentenyl acetone oxime in acetic acid with zinc dust at elevatedtemperatures, isolating from the reaction mixture an amine with theempirical formula of C H N and reducing this compound by a reagentselected from the group consisting of lithium aluminum hydride, hydrogenin the presence of a palladium catalyst, hydrogen in the presence of aplatinum catalyst, and zinc and hydrochloric acid.

6. A process for preparing cyclic amines which comprises treating n-cyclopentenyl acetone oxime in acetic acid with zinc dust at elevatedtemperatures, isolating from the reaction mixture an amine with theempirical formula of C H N 'and reducing this compound by a reagentselected from the group consisting of lithium aluminum hydride, hydrogenin the presence of a palladium catalyst, hydrogen in the presence of aplatinum catalyst, and zinc and hydrochloric acid to yield B-methyl-Z-azabicyclo-octane, and N-alkylating the product of said reductionstage by use of a methyl halide.

7. The process of claim 1, wherein the amines are separated byfractional crystallisation from benzine.

8. A process according to claim 1 wherein 4.60 parts by weight of n-cyclopentenyl acetone oxime are reacted with about 4.23 parts by weightof zinc dust.

9. A compound having the empirical formula C H N 7 produced by theprocess of claim 1.

2. A process for preparing cyclic amines which comprises treating A-cyclopentenyl acetone oxime in acetic acid with zinc dust at elevatedtemperatures, isolating from the reaction mixture an amine with theempirical formula of C H NO and reducing this compound by a 10. Acompound having the empirical formula C H NO produced by the processof'claim l.

11. The compound produced by the process of claim 2.

12. The compound produced by the process of claim 3.

13. The compound produced by the process of claim 5.

14. The compound produced by the process of claim 6.

Griot: Helv. Chimica Acta., volume 42, pages 67-72 (1959).

1. A PROCESS FOR PREPARING CYCLIC AMINES, WHICH COMPRISES TREATING$2-CYCLOPHENTENYL ACETONE OXIME IN ACETIC ACID WITH ZINC DUST ATELEVATED TEMPERATURES AND RECOVERING AND SEPARATING THE AMINES THUSPRODUCED FROM THE REACTION MIXTURE.
 9. A COMPOUND HVING TLHE EMPIRICALFORMULA C8H13N PRODUCED BY THE PROCSS OF CLAIM
 1. 0. A COMPOUND HAVINGTHE EMPIRICAL FORMULA C8H13NO PRODUCED BY THE PROCESS OF CLAIM 1.